MarvelD3 couples tight junctions to the MEKK1-JNK pathway to regulate cell behavior and survival

J Cell Biol. 2014 Mar 3;204(5):821-38. doi: 10.1083/jcb.201304115. Epub 2014 Feb 24.


MarvelD3 is a transmembrane component of tight junctions, but there is little evidence for a direct involvement in the junctional permeability barrier. Tight junctions also regulate signaling mechanisms that guide cell proliferation; however, the transmembrane components that link the junction to such signaling pathways are not well understood. In this paper, we show that MarvelD3 is a dynamic junctional regulator of the MEKK1-c-Jun NH2-terminal kinase (JNK) pathway. Loss of MarvelD3 expression in differentiating Caco-2 cells resulted in increased cell migration and proliferation, whereas reexpression in a metastatic tumor cell line inhibited migration, proliferation, and in vivo tumor formation. Expression levels of MarvelD3 inversely correlated with JNK activity, as MarvelD3 recruited MEKK1 to junctions, leading to down-regulation of JNK phosphorylation and inhibition of JNK-regulated transcriptional mechanisms. Interplay between MarvelD3 internalization and JNK activation tuned activation of MEKK1 during osmotic stress, leading to junction dissociation and cell death in MarvelD3-depleted cells. MarvelD3 thus couples tight junctions to the MEKK1-JNK pathway to regulate cell behavior and survival.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caco-2 Cells
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Cell Survival
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • MAP Kinase Kinase Kinase 1 / metabolism*
  • MAP Kinase Signaling System*
  • Membrane Proteins / metabolism
  • Membrane Proteins / physiology*
  • Osmotic Pressure
  • Tight Junctions / metabolism*


  • MARVELD3 protein, human
  • Membrane Proteins
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 1
  • MAP3K1 protein, human